The functional properties of hemoglobin in solution will be examined in order to derive plausible physical-chemical descriptions of these properties and to correlate the results with the in vivo oxygen uptake properties of intact red blood cells. The cooperative interaction of hemoglobin with ligands will be examined in terms of: (1) the effects of ligand size and stereochemistry; (2) the effects of substituents on the porphyrin ring; (3) the effects of iron coordination geometry and spin state; (4) effects of protein modification; and (5) the effects of intrinsic differences between the alpha and beta chain. These studies will allow the correlation of functional data with more specific structural intermediates, may provide explanations for certain apparent anomalies in experimental data, and will be useful for understanding the function of minor hemoglobin components and the clinical expression and consequences of certain hereditary hemoglobinopathies. The rates of ligand uptake by intact red cells, resealed erythrocyte membrane preparations, and artificial phospholipid bilayer vesicles will be measured by dual wavelength stopped-flow kinetic techniques. The objective of this study is to assess the importance of membrane diffusion resistance, hemoglobin concentration and modification, and hemoglobin-membrane interaction on the oxygen transport capacities of intact erythrocytes. Any substantial impairment of ligand uptake would have serious clinical manifestations (i.e., increased heart rate, polycythemia, etc.) since the rate of oxygen uptake by erythrocytes is already thought to limit, in part, the rate of gas exchange in the lungs and tissues.